Embryonic neurogenesis and differentiation in the hypothalamic feeding circuitry is under the control of a variety of diffused morphogens and intrinsic
transcription factors, leading to the unique structural and functional characteristics of each nucleus.

Scope of review:
The transcriptional regulation of the development of feeding neuroendocrine systems during the period of embryonic neurogenesis and differentiation will be
reviewed here, with a special emphasis on genetic and environmental manipulations that yield an adverse metabolic phenotype.

Major conclusions:
Emerging data suggest that developmental mechanisms can be perturbed not only by genetic manipulation, but also by manipulations to maternal nutrition
during the gestational period, leading to long-lasting behavioral, neurobiological, and metabolic consequences. Leptin is neurotrophic in the embryonic
brain, and given that it varies in proportion to maternal energy balance, may mediate these effects through an interaction with the mechanisms of
hypothalamic development.

Background/objectives:
Fasting dyslipidemia is commonly observed in insulin resistant states and mechanistically linked to hepatic overproduction of very low density lipoprotein
(VLDL). Recently, the incretin hormone glucagon-like peptide-1 (GLP-1) has been implicated in ameliorating dyslipidemia associated with insulin resistance
and reducing hepatic lipid stores. Given that hepatic VLDL production is a key determinant of circulating lipid levels, we investigated the role of both
peripheral and central GLP-1 receptor (GLP-1R) agonism in regulation of VLDL production.

Methods:
The fructose-fed Syrian golden hamster was employed as a model of diet-induced insulin resistance and VLDL overproduction. Hamsters were treated with the
GLP-1R agonist exendin-4 by intraperitoneal (ip) injection for peripheral studies or by intracerebroventricular (ICV) administration into the 3rd ventricle
for central studies. Peripheral studies were repeated in vagotomised hamsters.

Results:
Short term (7-10 day) peripheral exendin-4 enhanced satiety and also prevented fructose-induced fasting dyslipidemia and hyperinsulinemia. These changes
were accompanied by decreased fasting plasma glucose levels, reduced hepatic lipid content and decreased levels of VLDL-TG and -apoB100 in plasma. The
observed changes in fasting dyslipidemia could be partially explained by reduced respiratory exchange ratio (RER) thereby indicating a switch in energy
utilization from carbohydrate to lipid. Additionally, exendin-4 reduced mRNA markers associated with hepatic de novo lipogenesis and inflammation.
Despite these observations, GLP-1R activity could not be detected in primary hamster hepatocytes, thus leading to the investigation of a potential
brain-liver axis functioning to regulate lipid metabolism. Short term (4 day) central administration of exendin-4 decreased body weight and food
consumption and further prevented fructose-induced hypertriglyceridemia. Additionally, the peripheral lipid-lowering effects of exendin-4 were negated in
vagotomised hamsters implicating the involvement of parasympathetic signaling.

Methods/Results:
Using human Multipotent Adipose-Derived Stem cells, able to convert into brite adipocytes, we show that arachidonic acid strongly inhibits brite adipocyte
formation via a cyclooxygenase pathway leading to secretion of PGE2 and PGF2α. Both prostaglandins induce an oscillatory Ca++ signaling
coupled to ERK pathway and trigger a decrease in UCP1 expression and in oxygen consumption without altering mitochondriogenesis. In mice fed a standard
diet supplemented with ω6 arachidonic acid, PGF2α and PGE2 amounts are increased in subcutaneous white adipose tissue and associated with a
decrease in the recruitment of brite adipocytes.

Conclusion:
Our results suggest that dietary excess of ω6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the
"browning" process to take place.

Objective:
The C57Bl/6J (Bl/6J) mouse is the most widely used strain in metabolic research. This strain carries a mutation in nicotinamide nucleotide transhydrogenase
(Nnt), a mitochondrial enzyme involved in NADPH production, which has been suggested to lead to glucose intolerance and beta-cell dysfunction.
However, recent reports comparing Bl/6J to Bl/6N (carrying the wild-type Nnt allele) under normal diet have led to conflicting results using
glucose tolerance tests. Thus, we assessed glucose-stimulated insulin secretion (GSIS), insulin sensitivity, clearance and central glucose-induced insulin
secretion in Bl/6J and N mice using gold-standard methodologies.

Results:
Bl/6J mice have impaired GSIS compared to Bl/6N when glucose is administered intravenously during both a tolerance test and hyperglycemic clamp, but not in
response to oral glucose. First and second phases of GSIS are altered without changes in whole body insulin sensitivity, insulin clearance, beta-cell mass
or central response to glucose, thereby demonstrating defective beta-cell function in Bl/6J mice.

Conclusions:

The Bl/6J mouse strain displays impaired insulin secretion. These results have important implications for choosing the appropriate test to assess beta-cell
function and background strain in genetically modified mouse models.